Zinc improves mitochondrial respiratory function and prevents mitochondrial ROS generation at reperfusion by...

Serine 727 (Ser⁷²⁷) phosphorylation of STAT3 plays a role in the regulation of mitochondrial respiration. This study aimed to test if zinc could regulate mitochondrial respiration through phosphorylation of STAT3 at Ser⁷²⁷ in the setting of ischemia/reperfusion in the heart. Under normoxic conditions, treatment of isolated rat hearts with ZnCl₂ increased cytosolic STAT3 phosphorylation at Ser⁷²⁷ followed by phospho-STAT3 translocation to mitochondria. In isolated rat hearts subjected to 30 min regional ischemia followed by 20 min of reperfusion, ZnCl₂ given 5 min before the onset of reperfusion also increased mitochondrial phospho-STAT3. ZnCl₂ enhanced ERK phosphorylation and PD98059 reversed the effect of ZnCl₂ on STAT3 phosphorylation. ZnCl₂ improved the mitochondrial oxidative phosphorylation at reperfusion. This effect was abolished by STAT3S727A, a mutant in which Ser⁷²⁷ is replaced with alanine, in H9c2 cells subjected to hypoxia/reoxygenation. In addition, ZnCl₂ increased the mRNA level of the complex I subunit ND6, which was also reversed by STAT3S727A. Moreover, ZnCl₂ attenuated mitochondrial ROS generation and dissipation of mitochondrial membrane potential (ΔΨm) at reoxygenation through Ser⁷²⁷ phosphorylation. Finally, ZnCl₂ suppression of succinate dehydrogenase (SDH) activity upon the onset of reperfusion was nullified by the Ser⁷²⁷ mutation. In conclusion, zinc improves cardiac oxidative phosphorylation and inhibits mitochondrial ROS generation at reperfusion by increasing mitochondrial STAT3 phosphorylation at Ser⁷²⁷ via ERK. The preservation of ND6 mtDNA and the inhibition of SDH activity may account for the role of STAT3 in the beneficial action of zinc on the mitochondrial oxidative phosphorylation and ROS generation at reperfusion.